Advances in Transdermal Estrogen-Only Therapy for Vasomotor … · 2019. 1. 24. · women, and nearly 50% of surgically menopausal women.8,9 Sleep disturbances increase as the frequency

October 2013 S1AvAilAble At www.ObgmAnAgement.cOm

Advances in Transdermal Estrogen-Only Therapy for Vasomotor Symptoms

this resource is sponsored by noven therapeutics, llc and was reviewed prior to publication.

What are the key challenges for clinician providers who care for the older woman past reproductive age or those who are surgically menopausal?menopausal symptoms are a concern for a substantial num-ber of women in the United States. Annually, 11 million women reach the age of natural menopause—approximately 51.3 years.1,2 in addition, more than 500,000 women undergo a hysterectomy each year, with removal of the ovaries in more than 50%.3 whether menopause occurs naturally or is surgically-induced, more than 85% of these women

experience symptoms associated with estrogen deficiency, including, but not limited to, hot flushes and night sweats.4,5

How can moderate to severe hot flushes impact the day-to-day function of menopausal women?vasomotor symptoms (i.e., hot flushes and night sweats) are the number one complaint of menopausal women and the main reason that they seek treatment.6,7 vasomotor symp-toms (vmS) may also contribute to sleep difficulty, another common complaint affecting more than 40% of menopausal women, and nearly 50% of surgically menopausal women.8,9 Sleep disturbances increase as the frequency and sever-ity of vmS increases.10 in a related study by Ohayon, of the 982 women sampled, about half experienced mild hot flashes, a third moderate hot flashes, and 15.5% reported severe hot flashes. the world Health Organization defines severe hot flashes as occurring most of the time, characterized by a sen-

Author DisclosuresDr liu discloses that he receives grant or research support from noven, niH, nora therapeutics and Abbvie. He is a consultant to noven, Shionogi, and Ferring Pharmaceuticals.Dr minkin discloses that she is a consultant to noven, novo nordisk, bayer, enzymation therapies, Shionogi, and Pfizer.

James H. Liu, MDArthur H. bill Professor and chairUH macDonald women’s Hospitalcase medical centercase western Reserve University School of medicinecleveland, Ohio

Mary Jane Minkin, MDclinical Professor Department of Obstetrics, gynecology and Reproductive Sciences Yale University School of medicinenew Haven, connecticut

THE WOMEN’S HEALTH ALLIANCE

October 2013

continued on page S3

S2 October 2013

Please see accompanying full Prescribing Information including Boxed WArnIng.

INDICATIONminivelle™ (estradiol transdermal system) is indicated for treatment of moderate to severe vasomotor symptoms due to menopause.

IMPORTANT SAFETY INFORMATION

estrogens should not be used in women with undiagnosed abnormal genital bleeding; known, suspected, or history of breast cancer; known or suspected estrogen-dependent neoplasia; active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or history of arterial thromboembolic disease (e.g., stroke or mi); known anaphylactic reaction or angio-edema with minivelle, liver dysfunction or disease; known protein c, protein S, or antithrombin deficiency, or other known thrombophilic disorders; or known or suspected pregnancy.

estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

estrogens increase the risk of gallbladder disease. Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertri-glyceridemia or cholestatic jaundice occurs. monitor thyroid function in women on thyroid replacement therapy.

in clinical trials with vivelle® (estradiol transdermal system), the most common side effects (≥5%) were headache, breast tender-ness, back pain, pain in limb, nasopharyngitis, dyspepsia, nausea, sinusitis, and intermenstrual bleeding.

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIASee full prescribing information for complete boxed warning.

Estrogen-Alone Therapy

• There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens

• Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia

• The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT)

• The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older

Estrogen Plus Progestin Therapy

• Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia

• The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI)

• The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer

• The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older

http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203752lbl.pdf

October 2013 S3

Please see full Important Safety Information on page S2.Please see accompanying full Prescribing Information including Boxed WArnIng.

sation of heat with sweating, and causing the woman to stop her activity.9 Half (50.9%) of the women in the Ohayon study experienced both night sweats and daytime hot flashes.

Do we know more about the risks of hormone therapy since the initial Women’s Health Initiative (WHI) findings from 2002?the original reports from the wHi provided an understand-ing of the benefits and risks of hormone therapy (Ht).12,13 more detailed analyses of the wHi data, and results from subsequent studies help provide additional insight on the benefits and risks associated with treatment. Unlike the original reports from wHi, these analyses attempt to clarify the risk-benefit ratio of therapy and age and time since menopause with respect to the initiation and use of Ht.11, 14-16 Other evidence suggests that the dose and route of administration also affect the risks of Ht.15

A secondary analysis of the wHi data included 77.9% of participants in the conjugated estrogen-only (et) group (n=3778) and 78.4% of participants in the placebo group (n=3867) who continued into the postintervention extension phase and were followed for a mean of 10.7 years.14 One of the objectives of the extension was to examine the relation-ship of age at study randomization on health outcomes.14 As clinicians, it is important to understand that risk of disease can be calculated in several ways. the original and follow-up anal-yses demonstrated a trend for risk in terms of hazard ratios (FIGURE 1). when expressed in terms of absolute rate per 10,000 women annualized over the average follow-up of 10.7 years, women aged 50 to 59 who received et compared with women who received placebo had 13 fewer coronary heart disease (cHD) events. the women aged 60 to 69 who

received et did not experience a difference in events ver-sus those on placebo (plotted zero in FIGURE 1). by contrast, women aged 70 to 79 years who received et compared to women who received placebo had 6 excess events (P = 0.05 for every age interaction).14 Understanding the absolute risks of these events may allow clinicians to better counsel their patients on the risks and benefits associated with therapy.

How do we appropriately communicate these new findings on the benefits and absolute risks of estrogen therapy into a clinical context? experts in menopause management consider et with or without a progestogen to be the most effective treatment for moderate to severe vmS and related conditions.17 indeed, one of the primary indications for et is the treatment of moderate to severe vmS.17 estrogen alone is recommended for hyster-ectomized women, but women with an intact uterus should receive concomitant progestogen (ePt) to protect the endo-metrium from the risk of unopposed estrogen causing hyper-plasia and endometrial cancer.4,17 the wHi estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a nonsignificant trend toward reduced risk for cHD.18

What is the optimum duration of HT and how does it differ for estrogen alone versus estrogen plus progestogen?the recommendation for the duration of Ht differs for ePt and et. For ePt, the duration is limited by the increased risk of breast cancer and breast cancer mortality associated with 3 to 5 years of use.17 For et, a more favorable benefit-risk profile was observed during a mean of 7 years of use and 4 years of follow-up, findings that allow more flexibility in duration of use.17

What are the different routes of estrogen administration?All FDA-approved estrogen products are approved for the treatment of vmS, though the doses approved for vmS that have demonstrated efficacy vary by product.19 the most common routes for the administration of estrogen are oral and transdermal.4

et products may contain natural or synthetic conjugated equine estrogens (ce), 17β-estradiol (e2), or other synthetic estradiol derivatives.20 A number of oral and transdermal estro-gen products are available. there also are topical options, includ-ing several gels, an emulsion, and a spray, all of which contain 17β-estradiol (e2) (TABLE 1 and TABLE 2 on pages S4 and S5).

the wide variety of et products permits individualization of therapy, as recommended by the north American meno-pause Society (nAmS), the American Association of clinical endocrinologists (AAce), and the US Food and Drug Admin-istration.4,17,21 All agree that the lowest effective dose should be prescribed for the shortest duration of time, consistent with treatment goals and individual risks.5,17,21-23 the deci-sion to discontinue et should be made jointly by the health care provider and the patient. However, clinical experience indicates that some women may require extended therapy

Absolute Risk of Coronary Heart Disease (CHD) Events Associated With ET in the WHI Randomized Trial,

According to Age at Enrollment

*Women aged 60-69 who received ET did not experience a di�erence in events versus those on placebo (plotted zero here).

10

5

0

-5

-10

-15

*

■ 50-59 years ■ 60-69 years ■ 70-79 years

Abs

olut

e Ri

sk(D

i�er

ence

in C

HD

Eve

nts

vs P

lace

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r 10,

000

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FIGURE 1 Age-specific intervention results for a mean follow-up of 10.7 years14

Adapted from LaCroix AZ, et al. JAMA. 2011;305(13):1305-1314.

Hormone therapy (HT): A term that includes both estrogen monotherapy (ET) and estrogen + progestogen combination therapy (EPT)11

continued from page S1


tRAnSDeRmAl eStROgen-OnlY tHeRAPY

S4 October 2013


because of persistent symptoms.4,17,22 women choosing to continue et must be made aware of the risks and moni-tored appropriately.

Is there important counseling information for patients about potential short-term side effects of estrogen therapy?One of the best ways to ensure compliance with a recom-mended product is for the healthcare provider to fully inform the patient about the potential risks and side effects. this may help alleviate patient concerns and dispel any misconceptions they may have while providing an appropriate risk-benefit perspective. common side effects of et include headache, breast pain and tenderness, and nausea and vomiting.24 For a complete list of side effects and potential risks, clinicians should consult the labeling for the specific et formulation prescribed. the clinician should properly manage the patient’s expectations ahead of time. if the patient understands that she may be experiencing manageable side effects, this may reduce the likelihood that the patient will discontinue therapy without first consulting her clinician. in addition, it is advisable to schedule a follow-up visit to determine whether any dose adjustment is needed and to discuss any side effects that the patient may be experiencing. Patients should be reevaluated periodically (typically 3-6 months) to determine if ongoing treatment is still needed.

What advice should we provide to patients regarding the use of estrogen therapy?in addition to using an et product with proven efficacy for their symptoms, patients may want to learn how features of differ-

ent formulations fit in with their preferences. A wide variety of oral and transdermal et options are available.25 transdermal et options include gels, sprays, and patches. the gel formulations include 2 delivered via pump and 1 supplied in foil packets. An estradiol spray is approved at a dosage of 1 to 3 sprays per day for the treatment of moderate to severe vmS.25

considerations for the use of an oral option include potential interactions with food, as well as convenience in remembering to take the medication on a regular daily basis. transdermal patches also have considerations that should be discussed with patients if a patch is their desired form of therapy. Patches should only be applied to skin that is clean, dry, and free of any powder, oil, or lotion.18 the patch should be applied to a different area of the abdomen or buttocks each time. Patients should not use the same application site 2 times in the same week.18 Upon removal of the patch, if any adhesive residue remains on the skin, the area needs to dry for 15 minutes. then, patients can gently rub the area with oil or lotion to remove the adhesive from the skin.18 Finally, for other topical nonpatch products, there is a wait time before patients who use gels or sprays can bathe or swim. Users of gels and sprays need to allow at least 2 to 5 minutes for these products to dry before dressing, and users of gels must wash their hands after application.25 because all of the gels and sprays are alcohol-based, users are cautioned to avoid fire, flame, or smoking until they have dried.25 gels and sprays may have specific instructions regarding the application of sunscreen.

Specific product label information should be con-sulted to determine how best to counsel patients.25 cer-tainly, clinicians can advise a patient about et options that

TABLE 1 Oral estrogen therapy options for women with surgical menopause (i.e., those without a uterus): Products available in the United States20

Composition Available dosages/day (mg) FDA-approved indications

conjugated estrogens (1 brand) 0.3, 0.45, 0.625, 0.9, 1.25 PmO, vmS, vvA, He

Synthetic conjugated estrogens, A (1 brand)

0.3, 0.45, 0.625, 0.9, 1.25 vmS, vvA (0.3 mg/day dosage is indicated for vvA only)

Synthetic conjugated estrogens, b (1 brand)

0.3, 0.45, 0.625, 0.9, 1.25 vmS, vvA

esterified estrogens (1 brand) 0.3, 0.625, 1.25, 2.5 vmS, vvA, He

17β -estradiol (1 brand and various generics)

0.5, 1.0, 2.0 PmO, vmS, vvA, He (indications for tablets only)

estradiol acetate (1 brand) 0.45, 0.9, 1.8 vmS

estropipate (1 brand and various generics)

0.625 (0.75 estropipate, calculated as sodium estrone sulfate 0.625), 1.25 (1.5), 2.5 (3.0), 5.0 (6.0)

PmO, vmS, vvA, He

Composition and dosages are adapted from The North American Menopause Society. Hormone products for postmenopausal use in the United States and Canada. November 19, 2012. Indications are from manufacturers’ prescribing information.

PMO = Prevention of postmenopausal osteoporosis; VMS = Treatment of moderate to severe vasomotor symptoms associated with menopause; VVA = Treatment of moderate to severe symptoms of vulvar and vaginal atrophy; HE = Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.


October 2013 S5


may help address her specific menopausal symptoms. However, patients may not know what questions to ask; therefore, it is equally important for clinicians to proac-tively ask their patients about their concerns in order to best individualize treatment. For example, some patients may make decisions themselves based on incomplete information. A case in point comes from a telephone sur-vey of 670 women from an HmO following the news of the wHi in 2002.26 whereas 93% of those surveyed had heard about the long-term Ht study in the lay press, less than one-fourth understood the study in detail with regard to results on relative risks and benefits of et.26 Despite lack of knowledge of the study, over half of these women attempted to discontinue their Ht within 6 to 8 months of that study report.26 Unfortunately, many patients decide to stop Ht on their own, and often don’t inform their health care clinician about their questions or concerns. Patients may not realize that there is a chance of recurring symp-toms when Ht is discontinued, regardless of their age or duration of use, or whether et is discontinued abruptly or gradually.17,27-29 Symptom management should be bal-anced with an informed discussion regarding Ht and its associated risks and benefits.

What are the differences between oral and trans-dermal delivery of estrogen?For the treatment of vmS, dosages of oral conjugated estro-gen (ce) formulations range from 0.3 to 0.625 mg daily and micronized 17β-estradiol formulations range from 0.5 to 2.0 mg (TABLE 1).19 in contrast, dosages of transdermal estro-gen formulations approved for the treatment of vmS range from 0.025 to 0.1 mg/day (TABLE 2).18-20 Oral estrogens are absorbed from the gastrointestinal tract and transported to the liver, whereas transdermal estrogens are absorbed directly into the subcutaneous capillaries of the skin (FIGURE 2).4,19

when metabolized, oral estrogens produce an estrone/estradiol ratio that is 5 times higher than the ratio in menstruating women.30 the estrone/estradiol ratio resulting from transdermal estrogens is similar to the physiologic ratio in menstruating women (FIGURE 2 and TABLE 3 on page S6) .5,18,30-34 these differences do not imply differences in safety or efficacy.

What is the local tolerability and adhesion profile of the current drug-in-adhesive transdermal patch technology? the transdermal route of administration is ideally suited to small, potent, lipophilic drugs, which include estrogen. trans-

TABLE 2 Selected transdermal and topical estrogen therapy options for women with surgical menopause (i.e., those without a uterus): Products available in the United States20

Composition Delivery rate (mg/day) (mg) Dosing frequency FDA-approved indications

17 β-estradiol (E2) matrix patches

5 branded products 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 Once weekly PmO, vmS, vvA, He

0.025, 0.0375, 0.05, 0.075, 0.1 twice weekly

0.025, 0.05, 0.075, 0.1 twice weekly

1 branded product 0.0375, 0.05, 0.075, 0.1 twice weekly vmS only

2 branded products 0.025, 0.014 Once weekly PmO only

generic products 0.1, 0.05 Once or twice weekly vmS, vvA

17β -estradiol (1 brand and various generics)

0.5, 1.0, 2.0 PmO, vmS, vvA, He (indica-tions for tablets only)

Topical E2

3 branded gels 0.35 Daily application: 1 metered pump

vmS, vvA

0.0125 Daily application: 1-2 metered pumps

vmS

0.025, 0.05, 0.1 Daily application: 1 packet vmS

1 branded emulsion 0.05 (2 packets) Daily application: 2 packets vmS

1 branded spray 1.53-4.59 (one spray contains 1.53 mg e2 per 90 mcl)

initial dose: 1 spray, increase to 2 to 3 sprays/day as needed

vmS

References for composition and dosages are adapted from The North American Menopause Society. Hormone products for postmenopausal use in the United States and Canada. November 19, 2012. Indications are from manufacturers’ prescribing information.

PMO = Prevention of postmenopausal osteoporosis; VMS = Treatment of moderate to severe vasomotor symptoms associated with menopause; VVA = Treatment of moderate to severe symptoms of vulvar and vaginal atrophy; HE = Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.



S6 October 2013


dermal drug delivery has evolved from the first-generation reservoir patch introduced in 1986, followed by the solid-matrix system, and then the drug-in-adhesive transdermal patches employed in many of today’s estrogen products. (FIGURE 3 and FIGURE 4)

Absorption through the skin results in a gradual increase in serum drug concentration, which avoids the peaks and

troughs associated with oral administration, and that can be long-lasting. the estrogen release characteristics produce a range of plasma estradiol concentrations observed during the early follicular phase of the menstrual cycle.36

the newest drug-in-adhesive transdermal patch for et, minivelle® (estradiol transdermal system), contains estradiol in the same DOt matrix adhesive platform as vivelle-Dot®.18,37 minivelle is indicated for the treatment of moderate to severe vmS due to menopause. Four dosage strengths are avail-able to provide nominal in vivo delivery rates of 0.0375, 0.05, 0.75, or 1.0 mg of estradiol per day via the skin. each corre-sponding system has an active surface area of 2.48, 3.30, 4.95, or 6.6 cm2 and contains 0.41, 0.62, 0.83, 1.24, or 1.65 mg of estradiol USP, respectively.18

the DOt matrix delivery system is designed to release estradiol continuously.18,30 estradiol levels may increase above baseline with 4 hours after application.38 the wavy score pro-tective liner is designed for ease of handling during the appli-cation process. the adhesive layer is composed of estradiol mixed with acrylic and silicone in precise ratios to control the rate of delivery. the concentration gradient between the

FIGURE 2 Oral and transdermal drug delivery Oral Drug Delivery

Transdermal Drug Delivery

TABLE 3 Characteristics of oral and transdermal estrogens*

Oral estrogens (CEE and micronized 17β-estradiol)

Transdermal estrogens

largest total doses of estrogen5 Smallest total estrogen doses18,33

Absorbed from gastrointesti-nal tract and delivered directly to liver5,31

Absorbed directly into circula-tion via skin34

Produce estrone/estradiol ratios 5 times higher than in menstruating women32

Produce estrone/estradiol ratios similar to those in men-struating women30,32

*These differences do no imply differences in safety or efficacy of oral or transdermal agents.

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIASee full prescribing information for complete boxed warning.

Estrogen-Alone Therapy• There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens• Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia• The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein

thrombosis (DVT)• The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable

dementia in postmenopausal women 65 years of age and olderEstrogen Plus Progestin Therapy

• Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia• The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and

myocardial infarction (MI)• The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer• The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in

postmenopausal women 65 years of age and older



October 2013 S7


estradiol in the patch and skin results in highly efficient diffu-sion through the skin into systemic circulation.35

Patch application is twice-a-week.18 the recommended starting dose for patients initiating use of et for moderate to severe vmS is 0.0375 mg/day. when switching patients with vmS on vivelle-Dot® to minivelle®, use the same correspond-ing minivelle dose for the indication (1:1 switch).37

minivelle 0.05 mg/day provides a dose of estrogen that is 92% less than conjugated equine estrogens (Premarin®) 0.625 mg/day.37

minivelle (estradiol transdermal system) is bioequiva-lent to vivelle® which has demonstrated safety and efficacy for the treatment of vmS.37 in a single-dose, two-way cross-over study conducted in 96 healthy, non-smoking, non-fasting, postmenopausal women, minivelle (0.1 mg/day)

was bioequivalent to vivelle (0.1 mg/day) based on estra-diol exposure (AUc0-84) and estradiol peak concentration (cmax) following a single dose on the lower abdomen for 84 hours.18,37 Patients should not start using minivelle if they have unusual vaginal bleeding, currently have or have had certain cancers, had a stroke or heart attack, currently have or have had blood clots, currently have or have had liver problems, have been diagnosed with a bleeding disorder, are allergic to minivelle or any of its ingredients, or think they may be pregnant. the most common adverse events (≥ 5%) include headache, breast tenderness, back pain, pain in the limbs, nasopharyngitis, dyspepsia, nausea, sinusitis, and intermenstrual bleeding.18 estradiol pharmacokinetics were characterized in a separate open-label, single-center, randomized, single-dose, three-way, crossover study con-

Backing Layer

Drug Reservoir

Capillary Plexus

Dermis

Stratum Granulosum

Stratum Corneum

Rate Controlling MembraneAdhesive

FIGURE 3 reservoir patch FIGURE 4 Matrix patch

120 A = 0.1 mg per day

B = 0.05 mg per day

C = 0.025 mg per day100

80

60

Seru

m C

once

ntra

tion

(pg/

mL)

40

20

0-1 -0.5 0 0.5 1 1.5 2

Time (days)

2.5 3 3.5 4 4.5 5

FIGURE 5 Mean baseline-uncorrected estradiol serum concentration-time profile following a single dose of Minivelle® 0.1 mg/day (A), 0.05 mg/day (B), and 0.025 mg/day (C). (n=36)18

backing

estradiol and adhesive layer

Protective liner

in a dose-proportionality study, it was shown that concentrations increase linearly with increasing doses from smallest (0.025 mg/day) through a middle dose (0.05 mg/day) to the highest dose (0.1 mg/day).



S8 October 2013


ducted in 36 healthy, nonsmoking postmenopausal women (aged 40 to 65 years). minivelle patches delivering nominal estradiol of approximately 0.025 mg, 0.05 mg, and 0.1 mg per day were applied to the lower abdomen under fed condi-tions in a crossover fashion for 84 hours. the mean baseline-uncorrected estradiol serum concentrations of minivelle at three dosage strengths are shown in FIGURE 5 on Page S7.18,37

Reduced patch size: minivelle is currently the smallest et patch and is 34% smaller than vivelle-Dot® (FIGURE 6).39-41

Local tolerability profile: During the clinical pharmacol-ogy studies with minivelle, 35% or less of subjects experienced barely perceptible erythema. no transdermal systems were removed due to irritation. three subjects (2.2 %) reported mild discomfort while wearing minivelle (n=136).18

Adhesion data: the smooth, curved edges (FIGURE 7) may help prevent the minivelle patch from lifting or snagging asso-ciated with everyday wear. the minivelle patch stays in place during showering and exercising. in pharmacokinetic studies, nearly 100% of subjects reported complete adhesion over the wear period. this is based on combined data from a bio-equivalence and dose-proportionality study consisting of 208 observations.37

Overall summarymenopausal symptoms are a concern for a substantial num-ber of women in the United States, and hot flushes and night sweats are the number one complaint and the main reason that they seek treatment.6,7

while original reports from the wHi helped to provide an understanding of the benefits and risks of Ht, more recent and detailed analyses of the wHi data, as well as results from subsequent studies, help provide additional insight on the benefits and risks associated with treatment.11,12 these more recent analyses attempt to clarify the benefits and risks of therapy and age and time since menopause with respect to the initiation and use of Ht, as well as dose and route of administration.13-16

experts in menopause management consider et with or without a progestogen to be the most effective treatment for moderate to severe vmS.17 For ePt, the duration is lim-ited by the increased risk of breast cancer and breast cancer mortality associated with 3 to 5 years of use.17 For et, a more

favorable risk-benefit profile was observed during a mean of 7 years of use and 4 years of follow-up, findings that allow more flexibility in duration of use.17 the most common routes for the administration of estrogen are oral and transdermal. transdermal drug delivery has evolved from the first-genera-tion reservoir patch introduced in 1986, followed by the solid-matrix system, and then the drug-in-adhesive transdermal patches employed in many of today’s estrogen products. the newest drug-in-adhesive transdermal patch for et, minivelle (estradiol transdermal system), contains estradiol in the same DOt matrix adhesive platform as vivelle-Dot.18 minivelle is indicated for the treatment of moderate to severe vmS. Four dosage strengths are available to provide nominal in vivo delivery rates of 0.0375, 0.05, 0.75, or 1.0 mg of estradiol per day via the skin.18 the recommended dose for patients initi-ating use of et for moderate to severe vmS is 0.0375 mg/day. Patch application is twice-a-week.18

minivelle 0.05 mg/day provides a dose of estrogen that is 92% less than conjugated equine estrogens (Premarin®) 0.625 mg/day.37 minivelle is bioequivalent to vivelle and offers the same demonstrated efficacy.37 minivelle is the small-est patch currently available for et, and is 34% smaller than vivelle-Dot.37 in pharmacokinetic studies, nearly 100% of subjects reported complete adhesion over the wear period. this is based on combined data from a bioequivalence and dose-proportionality study consisting of 208 observations.37 minivelle may be a safe and effective treatment option for women who suffer from moderate to severe vasomotor symp-toms due to menopause.

FIGURE 7 Minivelle and its wavy score protective liner

FIGURE 6 Minivelle® (estradiol transdermal system) is currently the smallest patch available for ET

Dime and patches are proportional, but not shown at actual size

*mg/day

0.0375* 0.05* 0.075* 0.1*


October 2013 S9


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2. mcKinlay Sm, brambilla DJ, Posner Jg. Reprint of the normal menopause transi-tion. Maturitas. 2008;61(1-2):4-16.

3. Hall mJ, DeFrances cJ, williams Sn, golosinskiy A, Schwartzman A. national Hos-pital Discharge Survey: 2007 summary. national health statistics reports; no 29. Hyattsville, mD: national center for Health Statistics. 2010.

4. cobin RH and the AAce menopause guidelines Revision task Force. American Association of clinical endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocr Pract. 2006;12(3):315-317.

5. goodman nF, cobin RH, ginzburg Sb, Katz iA, woode De. American Association of clinical endocrinologists medical guidelines for the diagnosis and treatment of menopause. Endocr Pract. 2011;17(Suppl 6):1-25.

6. Freeman ew, Sammel mD, lin H, et al. Symptoms associated with menopausal transition and reproductive hormones in midlife women. Obstet Gynecol. 2007;110(2 Pt 1):230-240.

7. Dennerstein l, Dudley ec, Hopper Jl, guthrie JR, burger Hg. A prospective popu-lation-based study of menopausal symptoms. Obstet Gynecol. 2000;96(3):351-358.

8. Kravitz Hm, ganz PA, bromberger J, Powell lH, Sutton-tyrell K, meyer Pm. Sleep difficulty in women at midlife: a community survey of sleep in the menopausal transition. Menopause. 2003;10(1):19-28.

9. Ohayon mm. Severe hot flashes are associated with chronic insomnia. Arch Intern Med. 2006;166(12):1262-1268.

10. Kravitz Hm, Zhao X, bromberger Jt, et al. Sleep disturbance during the meno-pausal transition in a multi-ethnic community sample of women. Sleep. 2008;31(7):979-990.

11. Rossouw Je, Anderson gl, Prentice Rl, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s Health initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

12. Anderson gl, limacher m, Assaf AF, et al. effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the women’s Health initiative ran-domized controlled trial. JAMA. 2004;291(14):1701-1712.

13. Rossouw Je, Prentice Rl, manson Je, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297(13):1465-1477.

14. lacroix AZ, chlebowski Rt, manson Je, et al. Health outcomes after stopping con-jugated equine estrogens among postmenopausal women with prior hysterec-tomy: a randomized controlled trial. JAMA. 2011;305(13):1305-1314.

15. taylor HS, manson Je. Update in hormone therapy use in menopause. J Clin Endo-crinol Metab. 2011;96(2):255-264.

16. Santen RJ, Allred Dc, Ardoin SP, et al. Postmenopausal hormone therapy: an endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95(7 Suppl 1):s1-s66.

17. the north American menopause Society. the 2012 hormone therapy posi-tion statement of the north American menopause Society. Menopause. 2012;19(3):257-271.

18. minivelle (estradiol transdermal system) [package insert]. miami, Fl: noven Phar-maceuticals inc; 2012.

19. north American menopause Society. chapter 9. Prescription Hormonal therapies. in: Menopause Practice: A Clinician’s Guide. 4th ed. mayfield, OH: north American menopause Society; 2010:chap 9.

20. the north American menopause Society. Hormone products for postmenopausal use in the United States and canada. november 29, 2012. www.menopause.org /htcharts.pdf. Accessed June 26, 2013.

21. US Food and Drug Administration. Questions and answers for estrogen and estro gen with progestin therapies for postmenopausal women (updated). www.fda .gov/Drugs/DrugSafety/informationbyDrugclass/ucm135339.htm. Updated April 30, 2009. Accessed march 14, 2011.

22. American college of Obstetrics and gynecologists committee on gynecologic Practice. AcOg committee Opinion no. 420, november 2009: hormone therapy and heart disease. Obstet Gynecol. 2008;112(5):1189-1192.

23. Sturdee Dw, Pines A; international menopause Society writing group, et al. Updated imS recommendations on postmenopausal hormone therapy and pre-ventive strategies for midlife health. Climacteric. 2011;14(3):302-320.

24. US Food and Drug Administration. guidance for industry. noncontraceptive estrogen drug products for the treatment of vasomotor symptoms and vulvar and vaginal atrophy symptoms—recommended prescribing information for health care providers and patient labeling. www.fda.gov/downloads/Drugs/DrugSafety /informationbyDrugclass/ucm135336.pdf. november 2005. Accessed February 13, 2013.

25. US Food and Drug Administration web site. www.fda.gov. Accessed August 8, 2013. 26. ettinger b, grady D, tosteson An, Pressman A, macer Jl. effect of the women’s

Health initiative on women’s decisions to discontinue postmenopausal hormone therapy. Obstet Gynecol. 2003;102(6):1225-1232.

27. Ockene JK, barad DH, cochrane bb, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA. 2005;294(2):183-193.

28. brunner Rl, Aragaki A, barnabei v, et al. menopausal symptom experience before and after stopping estrogen therapy in the women’s Health initiative randomized, placebo-controlled trial. Menopause. 2010;17(5):946-954.

29. Haimov-Kochman R, barak-glantz e, Arbel R, et al. gradual discontinuation of hor-mone therapy does not prevent reappearance of climacteric symptoms: a ran-domized prospective study. Menopause. 2006;13(3):370-376.

30. coelingh bennink HJ. Are all estrogens the same? Maturitas. 2004;47(4):269-275.31. Kuhl H. Pharmacokinetics of oestrogens and progestogens. Maturitas. 1990;

12(3):171-197. 32. Scott Rt Jr., Ross b, Anderson c, Archer DF. Pharmacokinetics of percutaneous

estradiol. a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol. 1991;77(5):758-764.

33. climara [package insert]. wayne, nJ: bayer Healthcare Pharmaceuticals inc; 2007. 34. Potts RO, lobo RA. transdermal drug delivery: clinical considerations for the

obstetrician-gynecologist. Obstet Gynecol. 2005;105(5 Pt 1):953-961. 35. mantelle JA. Dot-matrix® technology. in: Rathbone mJ, Hadgraft J, Roberts mS,

lane me, eds. Modified-Release Drug Delivery Technology. vol 1. 2nd ed. new York, nY: informa Healthcare USA, inc; 2008:413-423.

36. balfour JA, Heel Rc. transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of meno-pausal complaints. Drugs. 1990;40(4):561-582.

37. Data on file. noven Pharmaceuticals, inc. miami, Fl.38. vivelle-Dot [package insert]. east Hanover, nJ: novartis Pharmaceuticals corp;

2004.39. european monthly Prescribing Reference. Hormone replacement therapy chart.

http://www.empr.com/hormone-replacement-therapy-chart/article/123738/. Updated June 14, 2013. Accessed October 29, 2012.

40. Pharmaceuticals and medical Devices Agency, Japan. Pharmaceuticals and medi-cal Devices Safety information, no. 252. november 2008. http://www.pmda.go.jp /english/service/pdf/precautions/PmDSi-252.pdf. Accessed november 9, 2012.

41. US Food and Drug Administration. estrogen and estrogen with progestin thera-pies for postmenopausal women. http://www.fda.gov/Drugs/DrugSafety/infor-mationbyDrugclass/ucm135318.htm#.U14ZzYbzknm.email. Updated June 22, 2010. Accessed October 29, 2012.

minivelle® is a registered trademark of noven therapeutics, llc.

All registered trademarks are the property of their respective owners.

© 2013 noven therapeutics, llc. All rights reserved.



S10 October 2013


October 2013 S11


Less skin exposedCauses almost no skin irritation and leaves almost no sticky residue behind on the skin4

Discreet design34% smaller than Vivelle-Dot® and about the size of a dime at the 0.0375 mg/day dose

Effective reliefEffectively relieves moderate to severe hot flashes and night sweats due to menopause4

For the treatment of moderate to severe vasomotor symptoms due to menopause

Good things come in small patches

Staying powerStays in place during showering and exercising, and round shape may help prevent snagging associated with everyday wear4

Visit www.minivelle.com to learn more and to find

out how eligible patients can save big on this small patch.*

*For eligible patients only. Restrictions may apply. See offer for the full terms and conditions.

Estrogens should not be used in women with undiagnosed abnormal genital bleeding; known, suspected, or history of breast cancer; known or suspected estrogen-dependent neoplasia; active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or history of arterial thromboembolic disease (e.g., stroke or MI); known anaphylactic reaction or angioedema with MINIVELLE, liver dysfunction or disease; known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; or known or suspected pregnancy.Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. Estrogens increase the risk of gallbladder disease. Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs. Monitor thyroid function in women on thyroid replacement therapy.In clinical trials with Vivelle® (estradiol transdermal system), the most common side effects (≥5%) were headache, breast tenderness, back pain, pain in limb, nasopharyngitis, dyspepsia, nausea, sinusitis, and intermenstrual bleeding.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the following pages.Please see adjacent page for references.

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIASee full prescribing information for complete boxed warning.Estrogen-Alone Therapy• There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens• Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia• The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT)• The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal

women 65 years of age and olderEstrogen Plus Progestin Therapy• Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia• The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI)• The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer• The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women

65 years of age and older

INDICATIONMINIVELLE® (estradiol transdermal system) is indicated for treatment of moderate to severe vasomotor symptoms due to menopause.


From the manufacturer of Vivelle-Dot®

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Advances in Transdermal Estrogen-Only Therapy for Vasomotor … · 2019. 1. 24. · women, and nearly 50% of surgically menopausal women.8,9 Sleep disturbances increase as the frequency